Compounds of formula (D) are known and are known to possess utility as platelet-activating factor (PAF) antagonists ##STR2##
Platelet-activating factor (PAF) has recently been identified as an acetyl glyceryl ether phosphorylcholine (AGEPC), i.e., 1-O-hexadecyl/octadecyl-2acetyl-sn-glyceryl-3-phosphoc holione (Hanahan D. J., etal., J. Biol. Chem. 225:5514, 1980). PAF has been linked to various biological activities and pathways making it one of the important mediators responsible for a variety of physiological processes including activation or coagulation of platelets, pathogenesis of immume complex deposition, smooth muscle contraction, inflammation, hypotension, shock, pain, edema as well as respiratory, cardiovascular and intravascular alterations. These physiological processes are in turn associated with a large group of diseases, for example, inflammatory disease, cardiovascular disorder, hypotension, shock, psoriasis, allergic and skin diseases, asthma, lung edema, peptic or stomach ulcer, dental pain, and adult respiratory distress syndrome.
Some compounds of formula (D) as well as their utility as PAF antagonists and their method of preparation are disclosed in U.S. Pat. No. 4,539,335 which issued on Sept. 3, 1985; E. P. 0 199 324, which published on Oct. 29, 1986; E. P. 0 322 033, published on June 28, 1986copending U.S. application Ser. Nos. 362,919, filed June 8, 1989 and 505,712 filed Apr. 11, 1990 all of which are hereby incorporated by reference.
Preparation of compounds of formula (D) is achieved via an acid catalyzed cyclization of a 1,4-diaryl-1,4-butanediol. This method, however, produces an isomeric mixture of cis and trans 2,5-diaryl tetrahydrofurans. See Tetrahedron Letters, 29, p. 6211 (1988). In contrast, the optically pure 5-aryl-butyro-lactones of the present invention are readily converted in a stereoselective reaction to a single physiologically active trans-isomer.
Some 2,5-diaryltetrahydrofurans have been prepared from 5-aryl substituted furanosides via a direct lactol activation with TMS-Br followed by coupling with an organometallic partner. See J. Am. Chem. Soc., 109, p. 7925 (1987). However, this method, when applied to electron-rich aromatic ring systems such as 3,4,5-trimethoxyphenol, produces low yields and is accompanied by significant side products.
Preparation of a furanosyl bromide from a furanosyl acetate with trimethylsilyl bromide has also been described. See Tetrahedron Letters, p. 513 (1981). Unfortunately, it is our experience that this technique leads to incomplete bromination with a consequent loss of yield and purity in the subsequent coupling reaction.
In contrast to the prior art, the instant process provides an efficient means to produce optically pure trans-2,5-diaryltetrahydrofurans from optically pure 5-aryl-.gamma.-butylrolactones in high yield with high stereoselectivity (trans:cis greater than 75:1) and high degrees of regiocontrol with respect to substitution on the aromatic ring.
Accordingly, the present invention is directed to the preparation of the most potent isomers of known or novel tetrahydrofuran derivatives as PAF antagonists and use them for the treatment of various diseases including prevention of platelet aggregation, hypotension, inflammation, asthma, lung edema, adult respiratory distress syndrome, various shock syndromes, cardiovascular disorders and other related skeletal-muscular disorders, graft-host rejection, nephritis, pancreatitis and lupus.